Practice Guidelines for Cardiovascular Fitness and Strengthening Exercise Prescription After Burn Injury

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1 ORIGINAL ARTICLE Practice Guidelines for Cardiovascular Fitness and Strengthening Exercise Prescription After Burn Injury Bernadette Nedelec, BSc OT(c), PhD,* Ingrid Parry, MS, PT, Hernish Acharya, BSc, MD, FRCPC, Lynne Benavides, OT/CHT, Sara Bills, PT,# Janelle L. Bucher, OTR/L,** Joanne Cheal, BMR, OT, Annick Chouinard, BSc, PT, Donna Crump, PT, Sarah Duch, PT, Matthew Godleski, MD, Jennifer Guenther, MSPT, Catherine Knox, OTR/L, Eric LaBonte, PT,## David Lorello, DPT,*** J. Xavier Lucio, MS OTR/L, Lori E. Macdonald, MSc PT, Jennifer Kemp-Offenberg, OTR/L, Candice Osborne, OT, Kara Pontius, PT, Miranda Yelvington, MS,OTR/L, BCPR, Ana de Oliveira, BSc, Lorie A. Kloda BA, MLIS, PhD The objective of this review was to systematically evaluate the available clinical evidence for the prescription of strength training and cardiovascular endurance exercise programs for pediatric and adult burn survivors so that practice guidelines could be proposed. This review provides evidence-based recommendations specifically for rehabilitation professionals who are responsible for burn survivor rehabilitation. Summary recommendations were made after the literature was retrieved by systematic review, was critically appraised by multiple authors and the level of evidence determined in accordance with the Oxford Centre for Evidence-based Medicine criteria. 1 Although gaps in the literature persist and should be addressed in future research projects, currently, strong research evidence supports the prescription of strength training and aerobic conditioning exercise programs for both adult and pediatric burn survivors when in the presence of strength limitations and/or decreased cardiovascular endurance after evaluation. (J Burn Care Res 016;37:e539 e558) From the *School of Physical and Occupational Therapy, McGill University, Montreal, Quebec, Canada; Centre de recherche, Centre hospitalier de l Université de Montréal (CRCHUM), Quebec, Canada; Hôpital de réadaptation Villa Medica, Montreal, Quebec, Canada; Shriners Hospitals for Children, Northern California, Sacramento; Division of Physical Medicine and Rehabilitation, Department of Medicine, University of Alberta, Glenrose Rehabilitation Hospital, Edmonton, Alberta, Canada; Rhode Island Hospital, Rehabilitation Medicine, Providence; #University of Nebraska Medical Center, Omaha, Nebraska; **University of Washington, Seattle, Washington; Alberta Health Services, Foothills Medical Centre, Calgary, Canada; Parkland Health & Hospital System, Dallas, Texas; Westchester Medical Center, Valhalla, New York; Medical Director of Inpatient Rehabilitation, University of Colorado Hospital, Aurora, Colorado; Children s Hospital Colorardo, Aurora, Colorado; ##Connecticut Burn Center, Bridgeport Hospital, Bridgeport, Connecticut; ***Arizona Burn Center, Phoenix, Arizona; University of Utah Burn Center, Salt Lake City, Utah; Shriners Hospitals for Children, Galveston, Texas; University of Texas Medical Branch, Galveston, Texas; Arkansas Children s Hospital Burn Center, Little Rock, Arkansas; and Library, McGill University, Montreal, Quebec, Canada. This study was supported by the Edith and Richard Strauss Foundation. Address correspondence to Bernadette Nedelec, PhD, McGill University, Faculty of Medicine, 3654 Promenade Sir William Osler, Montreal, Quebec, Canada H3G 1Y5. bernadette.nedelec@mcgill.ca. Copyright 015 by the American Burn Association X/015 DOI: /BCR RECOMMENDATIONS Standards There are 0 reports in the literature evaluating exercise program prescription for burn survivors; 14 were randomized controlled trials (RCTs), 11 included pediatric burn survivors, and three included adult burn survivors. All of these studies found the prescription of exercise programs to be advantageous. The clinical outcomes that showed significant improvement in the RCTs included aerobic capacity, functional outcomes, lean body mass (LBM), mobility evaluations, occupational performance, pulmonary function, resting energy expenditure, strength, total work volume, treadmill times, and weight. All exercise training programs took place at burn centers; however, most included additional in-hospital standard of care (SOC) treatment components provided by burn team members. Many of these outcomes may have improved, in part, due to the quality and quantity of in-hospital SOC treatments compared with the outpatient community or homebased programs that were not quantified. It is our e539

2 e540 Nedelec et al November/December 016 recommendation that further RCTs be conducted that are entirely in-hospital or community-based. Recommended Practice Guidelines Burn survivors strength and cardiovascular endurance should be evaluated in individuals 7 years of age and older. Those who test below normal levels should be prescribed a supervised resistance and/or aerobic exercise program. Exercise programs may begin as early as immediately postdischarge from acute care and as late as 14 years after burn. Exercise programs should last 6 to 1 weeks for adults and up to 1 weeks for children. Studies have not extended beyond 1 weeks therefore it is not known whether longer exercise programs would be more beneficial. OVERVIEW Purpose The purpose of this review was to formulate guidelines for practice, based on the strength of the published evidence evaluating the benefit of exercise programs designed to increase the cardiovascular fitness or muscular strength of adult and/or pediatric burn survivors. Users These guidelines are designed to aid burn care team members (exercise physiologists, kinesiologists, occupational therapists [OT], physicians, physiotherapists [PT], etc.), who are responsible for the prescription of exercise programs as a component of burn survivor rehabilitation programs. In addition, the recommended guidelines can be implemented by health professionals who do not routinely treat burn patients at their facilities, such as community-based fitness centers, schools, rural facilities, etc. Clinical Problem Improvements in acute care and surgical management of burn survivors have resulted in increased survival rates. 5 As more individuals recover from major burn injuries there has been an increased focus on rehabilitation to ensure that optimal function and quality of life is achieved. 6,7 The need and potential value of cardiovascular endurance and strengthening exercise programs for burn survivors is particularly pertinent after prolonged periods of immobilization during acute care and the characteristic physiological responses to burn injury, such as marked hypermetabolism and skeletal muscle catabolism When comparisons have been made between nonburned children relative to pediatric burn survivors, it has been shown that their aerobic capacity, LBM, 1 strength, 1 14 quadriceps size, gait parameters, 14 pulmonary function, and treadmill times 15,16 are significantly reduced in pediatric burn survivors. Comparisons of nonburned adults with adult burn survivors have additionally shown that aerobic capacity, 17,18 ambulation speed, 19 physical activity participation, 17 pulmonary function, 17,0 and strength 19,1, are significantly reduced and oxygen consumption elevated in adult burn survivors. Currently, the resources required, such as testing and training equipment and rehabilitation personnel, to offer rehabilitation programs that continue for weeks or months after discharge from acute care are lacking at most burn centers. Thus, the objective of this review was to systematically evaluate the available evidence examining the effectiveness of exercise programs to increase cardiovascular fitness or muscular strength in adult and/or pediatric burn survivors so that practice guidelines can be developed that specifically describe the required rehabilitation interventions and resources. PROCESS The steps taken to develop the practice guidelines reported here are those outlined by Bowker et al. 3 These steps included setting up a guideline development group, forging links with stakeholder groups, agreeing on the scope of the guidelines, formulating a clinically relevant PICO (population, intervention, condition, outcome) question, searching the literature for evidence, systematically appraising the evidence found, and making recommendations. The guideline development group consisted of an international assembly of OTs, physicians, and PTs who were members of the American Burn Association Rehabilitation Committee, and clinicians recruited from the American Burn Association. This group met at the American Burn Association meeting in March 014 for a practice guidelines development workshop where the steps associated with the development of practice guidelines were reviewed and several practice sessions, focused on critiquing the evidence, were performed until participants were comfortable with the critique form and process. The scope of the guideline is limited to the PICO question: Does exercise increase the cardiovascular fitness and/or muscular strength of adult and/or pediatric burn survivors?

3 Volume 37, Number 6 Nedelec et al e541 Search Strategy The literature search was designed to identify studies that focused on patients, either adults or children, who had sustained a burn injury and undergone a treatment involving exercise. All outcome measures that evaluated strength and cardiovascular endurance were considered. A broad literature search was conducted in the following bibliographic databases: MEDLINE, the Cumulative Index of Nursing & Allied Health Literature (CINAHL), EMBASE, Allied and Complementary Medicine (AMED), Pro- Quest Dissertations and Theses, Web of Science, OTseeker and PEDro, from the dates of inception until November 014. Search results were limited to records available in either English or French. The search strategy was designed and conducted by a medical librarian (LAK) as described in Appendix. The search strategy was later validated by the librarian; all 0 citations included in the practice guidelines were indexed in the Medline database and retrieved by the search. The combined total of results retrieved from the databases was 3090; 815 duplicates were removed, yielding 75 records for eligibility screening. Two additional publications were retrieved by scanning reference lists in the articles reviewed, bringing the total number of unique citations and abstracts that were screened to 77. Selection for Inclusion Since studies focusing on this clinical question were expected to be sparse, all study designs that provided original data on burn survivors were selected. The title and abstract of each article were assessed by two individuals for inclusion. Only full-length, primary articles were selected for review, with review articles being excluded to allow the critical appraisal of original publications; however, the reference list of review articles were scanned as described above. Ultimately, 5 articles were deemed appropriate for the full review process. Figure 1 maps out the records that were identified and depicts the flow through the phases of identification, screening for exclusion and inclusion in full-review as recommended by the PRISMA Statement. 4 Data Extraction and Analysis All studies were systematically critiqued and scored by at least two independent reviewers, drawing on Figure 1. PRISMA flow diagram mapping out the number of records identified, screened, assessed for eligibility, and included in the full review process and synthesis.

4 e54 Nedelec et al November/December 016 Table 1. Evidentiary Table: Evaluation of the Quality of Intervention Studies Sample Outcomes Citation Study Purpose Literature Review Design Size Details Justified Reliable Valid Detailed Description Ahmed et al (011) 1 1 CC Al-Mousawi et al (010) 1 1 RCT 1* Cronan et al (1990) 0 1 CC Cucuzzo et al (001) 1 1 RCT 1* de Lateur et al (007) 1 1 RCT Ebid et al (01) 1 1 RCT Ebid et al (014) 1 1 RCT 33* Ebid et al (01) 1 1 RCT Grisbrook et al (01) 1 1 CC Grisbrook et al (013) 1 1 CC Hardee et al (014) 1 1 RCT 47* Paratz et al (01) 1 1 Non-RCT Parrot et al (1988) 1 1 HC Porro et al (01) 1 1 RCT * Porro et al (013) 1 1 RCT 58* Prkzora et al (007) 1 1 RCT 51* Suman et al (00) 1 1 RCT 51* Suman et al (001) 1 1 RCT 35* Suman et al (003) 1 1 RCT 44* Suman et al (007) 1 1 RCT 0* Design: CC, case-controlled study; HC, historically controlled studies; non-rc, nonrandomized controlled cohort/follow-up study; RCT, randomized, controlled, trial. YES = 1; NO = 0; N/A = 0. *Pediatric burn survivors. the critical appraisal form designed by Law et al. 5 Fourteen items comprised in the scoring of this form relate to study purpose, literature review, study sample, outcomes, interventions, results, conclusions, and clinical implications. The two to three reviewers independently extracted details required to complete the critical appraisal form. Each item was rated numerically as (1) for Yes and (0) for No or Not Applicable. A total score was then calculated and compared with the other reviewers results. If there were minor differences (± points), the discrepancies were discussed until a consensus was reached. When larger differences occurred, an additional reviewer was called upon to critique the article and consensus was achieved among all reviewers. After this process, five articles were removed,6 9 because the authors clinical question was not addressed. SCIENTIFIC FOUNDATION Study Characteristics Table 1 summarizes the critique results for the 0 retained citations. Citations are categorized based on the population of patients included: (1) pediatric burn survivors only (denoted by single asterisk) and () adult burn survivors. As shown on the last column of this table, /0 citations (10%) received a score of <5 out of a possible total score of 14 but were included for completeness sake. Of the remaining citations 18 (90%) received a score 10 therefore are considered high quality studies. Table summarizes the study characteristics, results, and level of evidence for each of the 0 citations. Fourteen were RCTs, 1,14,16,19,31,3,34 36,38,41 44 one was a follow-up study, 39 four were case control studies, 0,30,33,37 and one a historically controlled study. 40 The sample sizes of all studies ranged from 16 to. Those including only pediatric participants ranged from 0 to while those with only adult participants ranged from 16 to 40. Sample size of the RCTs ranged from 1 to for those that included only pediatric participants and 31 to 40 for those that included only adult participants. The level of evidence was assigned according to the updated Oxford Centre for Evidence-based Medicine Levels of Evidence. 1 Pediatric Burn Survivor Studies Eleven of the 0 publications included in this review specifically addressed exercise prescription

5 Volume 37, Number 6 Nedelec et al e543 Intervention Results Contamination Co-intervention Statistical Significance Analysis Appropriate Clinical Importance Drop Outs Reported Conclusions Appropriate Total Score for pediatric burn survivors. Of these 11, 10 were carried out at the Shriners Hospital for Children, Galveston. All of the pediatric studies were RCTs and all received a rating of between 10 and 14 of 14 on the critique form. The prescribed resistance and/or aerobic exercise program had positive benefits, that are outlined in detail in Table, for a number of outcome measures including bone mineral content, 41 gait measures, 14,34 LBM, 1,31,3,38,41,43,44 pulmonary function, 16 quad size, 14 resting heart rate, 34 strength, 1,14,31,3,34,41 44 total work volume, 3,34 treadmill time, 16,3 and VO peak. 1,16,3,38,4,43 Two pediatric studies 6,9 were excluded from full review and incorporation into the final recommendation as they did not respond directly to the PICO question but did nonetheless demonstrate benefits from exercise for the outcomes that they examined. No adverse events were reported in any of these studies. Adult Burn Survivors There were several case series published in 1988 and 1990 that reported on the benefits of exercises or exercise programs specifically prescribed for burn survivors 33,40 but had many methodological limitations that were identified during the critique (Table 1). Since 007, there have been seven additional reports that were rated between 11 and 14 of 14. Three were case control studies, one was a follow-up study and three were RCTs. The prescribed resistance and/or aerobic exercise program had positive benefits, that are outlined in detail in Table, for a number of outcome measures including function, 0,39 gait measures, 19,39 LBM, 37 quality of life, 39 strength, 19,30,36,37,39 total work volume, 19 and VO max or peak. 0,39 One case control study, which was published in two different manuscripts with two different sets of outcomes reported in each, 0,37 reported an improvement with exercise but the improvement in the burn survivor group did not significantly differ from the improvement reported in their healthy controls. This group also reported on the impact of the exercise program on the participants self-reported quality of life 8 but this article was excluded from full review as it did not include any muscle strength or cardiovascular fitness measure, therefore did not respond to the PICO question. Outcome Measures The outcome measures that were used in these reports varied across studies. Those outcomes that

6 e544 Nedelec et al November/December 016 Table. Characteristics of Included Studies Authors Design Sample Outcome Measures Intervention Results Level of Evidence Ahmed et al Case control (011) 30 study n = 30 males (burn survivors = 15; healthy = 15) Mean age (yrs): burn s urvivors = 4.4; healthy = 4.8 %TBSAB: range Deep partial thickness anterior thigh burn Baseline: 1 5 days post-burn Strength (Biodex System-3 dynamometer) Evaluated at baseline and 6 weeks post-training 6-week treatment period ( /5) Ex: isokinetic strengthening Burn survivors and healthy subjects eccentric and concentric peak torque 30 and 90 /sec significantly improved % peak torque improvement was significantly greater for burn survivors than healthy subjects for eccentric 90ᵒ/sec and 30ᵒ/sec as well as concentric 30ᵒ/sec Peak torques were significantly greater for healthy subjects during concentric peak torques at 30 and eccentric torques at 30 and 90 In 011, Ahmed et al 30 performed a case-controlled follow-up study where a group of burn survivors and healthy participants were evaluated and then trained with exercises on an isokinetic dynamometer. After 6 weeks, of twice-per-week training, the eccentric and concentric muscle peak torque improved in both groups. The authors reported a significantly greater percentage of improvement for the burn survivors as compared with the healthy participants for eccentric contractions at both 30 and 90 per second and concentric contractions at 30 per second after training. 4 Al-Mousawi et al (010) 31 RCT n = 1 (Ex = 11, SOC = 10) Mean age (yrs): Ex = 1.; SOC = 13.7 Mean %TBSAB: Ex = 61; SOC = 56 Baseline: 6 mos post-burn REE LBM (DEXA) Strength (Biodex System-3 dynamometer: isokinetic) Height, weight 1-week treatment period SOC: same as Suman et al (001) Ex: (Figure ) Mean weight gain was significant for the Ex group, but no difference between groups No significant difference in the mean change in REE or percent predicted REE Subjects in the Ex group gained significantly greater LBM, even when normalized to height Ex group demonstrated significantly greater strength improvements, which persisted when normalized to LBM index In 010, Al-Mousawi et al 31 reported on a study using the exercise program described in Figure plus SOC compared with SOC only. The authors confirmed previous findings that LBM and strength improved but contrary to their previous findings 3 they reported that REE did not significantly increase with time in either group and that there was no significant difference between groups. Unlike their previous publication they normalized the REE measures to the corresponding changes in LBM, which resulted in the differences in REE becoming negligible, thus, exercise training did not exacerbate postburn hypermetabolism. (Continued )

7 Volume 37, Number 6 Nedelec et al e545 Table. (Continued ) Authors Design Sample Outcome Measures Intervention Results Level of Evidence Cronan et al Case control (1990) 33 study n = 16 (8 isokinetic; 8 isometric/ isotonic) patient-matched joints with full AROM Age range: 0 40 yrs %TBSAB: range 9 64 Baseline: 5 9 mos post-burn Strength (Cybex II dual isokinetic dynamometer) SOC: splinting, stretching, isometric, and isotonic work loads Ex: cardiovascular training and isokinetic protocol % deficit of peak torque was less in Ex group compared with SOC group for all joints tested No statistical analysis Cronan et al 33 compared burn survivors who had received SOC to burn survivors who had received SOC plus cardiovascular and strength training utilizing the isokinetic dynamometer. The patients served as their own controls by comparing an involved extremity to an uninvolved extremity. Those who received exercise training and SOC performed better when tested on an isokinetic dynamometer than the comparison joint. The authors report significant peak torque deficit in the nonisokinetic treatment group, although no statistical analyses were reported. In addition, details of the study population and intervention program were extremely limited. Cucuzzo et al (001) 34 Mean age (yrs): 10.6; (range RCT n = 1 (Ex = 11; SOC = 10) ) %TBSAB: mean 59.7; range Baseline: 6 mos post-burn Weight, height, resting heart rate, 6 MWT Strength (3RM) Evaluated at baseline & 1 weeks later (6 and 9 mos post-burn) 1-week treatment period SOC: OP OT and PT twice daily 1 hr Ex: Figure except aerobic exercise 3 / week plus OT and PT daily 1 hr, school 3 hrs/d, play therapy and psychological counselling as necessary Significant change for the following outcomes: weight Ex group and SOC group, resting heart rate for the Ex group, 3RM for the Ex group (biceps, triceps, forearms, quadriceps, hamstrings) and SOC group (forearms, quadriceps, hamstrings), total volume work for the Ex and SOC group, 6MWT for the Ex and SOC group Improvements were significantly greater for the Ex than SOC group for: 3RM (hamstrings), total volume work, 6MWT Cucuzzo et al 34 reported on 1 participants that were randomized to either an exercise group or a SOC group. The baseline age, percent burn, height, weight, and resting heart rate did not significantly differ between groups. The post-treatment evaluation revealed that weight, total volume of work, and the 6-minute walk test increased significantly in both groups. The resting heart rate improved in the exercise group but not the SOC group. All five of the 3RM increased for the exercise group and three of the five for the SOC group. The group comparisons revealed significant differences between groups for hamstring 3RM, total volume of work and the 6-minute walk test. There were no adverse events or dropouts. delateur et al (007) 35 SOC = 11) RCT n = 35 (WTQ = 13; WTT = 11; Mean age (yrs): WTQ = 35.4; WTT = 43.5; SOC = 34.9 Mean %TBSAB: WTQ = 19.5; WTT = 16.8; SOC = 1.6 Max aerobic capacity (VO max ) Evaluated at baseline and 1 weeks 1-week treatment period SOC: OT and PT (ROM, massage, splinting, stretching, strengthening, mobility training, ADL training) SOC + WTQ SOC + WTT WTT and WTQ group: significant improvements in aerobic capacity (VO max ) from baseline to 1/5 and compared with SOC but not between groups SOC group: no significant improvement in aerobic capacity No adverse effects reported 4 (Continued )

8 e546 Nedelec et al November/December 016 Table. (Continued ) Authors Design Sample Outcome Measures Intervention Results Level of Evidence In 007, de Lateur et al 35 published the first RCT involving adult burn survivors. Participants were randomly assigned to one of three groups: (1) functional restoration (SOC); () work-to-tolerance group (WTT); and (3) work-to-quota (WTQ). The WTT group performed aerobic exercise at their target heart rate for as long as tolerated to a maximum of 30 minutes. The WTQ group exercised to preset quotas that gradually increased the exercise intensity. The maximal oxygen consumption of the WTT and WTQ groups significantly increased more than the SOC group. There was, however, no difference between the two exercise groups. Ebid et al (01) 36 SOC = 16) RCT n = 31 adults (Ex = 15; Mean age (yrs): Ex = 35.86; SOC = %TBSAB range: Baseline: ~50 d post-burn Strength (Biodex isokinetic dynamometer) Evaluated at baseline and 8 weeks later Matched healthy controls compared with baseline measures 8-week treatment period SOC: home program (ROM, splinting, stretching of LE, daily walking, functional ambulation, resistance exercises, ADL training) Ex: whole body vibration 3 /5 Knee and ankle strength was significantly greater in healthy subjects compared with burn survivors Knee and ankle strength significantly increased in both treatment groups across time Mean % change in strength was significantly greater for Ex group compared with SOC In 01, Ebid et al 36 conducted a RCT studying two groups of burn survivors who received either whole body vibration (WBV) plus SOC or SOC only. Whole body vibration involved the subject standing in a 90 squat position on a vibrating platform. The authors measured strength outcome and compared it to healthy, matched controls at baseline. Both groups demonstrated an increase in strength after 8 weeks of treatment, although the WBV group s strength gains were significantly greater than the SOC group. The burn survivors strength was significantly reduced relative to the healthy controls at baseline but nearly returned to the healthy, matched, controls after the 8 weeks. Ebid et al (014) 14 healthy = 0) RCT n = 33 (Ex = 16; SOC = 17; Mean age (yrs): Ex = 13.46; SOC = 13.6; healthy = 14. Mean %TBSAB: Ex = 48.86; SOC = 4.4 LE burns Strength (Biodex System-3 dynamometer) Quadriceps size (tape measure) Gait parameters (GAITRite system) Evaluated at baseline and 1 weeks later Matched healthy controls compared with baseline measures 1-week treatment period SOC: home program Ex: SOC + 3 /5, treadmill warm-up, hotpacks, stretching, isokinetic exercises Quad strength: significantly less for burn survivors compared with healthy subjects at baseline; significantly increased for Ex and SOC group but significantly more for Ex Quad size: significantly greater for healthy subjects compared with burn survivors at baseline; significant increase in Ex group All gait parameters: significantly different for burn survivors compared with healthy subjects at baseline; significantly increased for Ex and SOC but significantly more for Ex group The one pediatric study not conducted by the Galveston group was a RCT in 014, by Ebid et al. 14 Children with lower extremity burns were randomized to either a 1 week isokinetic quad strengthening program in addition to SOC or just SOC. They evaluated the effect of an isokinetic quad strengthening program on the size and strength of the quadriceps and on gait parameters. All measures significantly improved for both groups during the 1-week treatment period except quad size for the SOC group. The improvements were significantly greater for the exercise group compared with the SOC group for all measures. They also compared baseline measures of quad size and strength and gait parameters to age-matched healthy children. All baseline measures differed significantly from those of healthy children. It should be noted that the resistance training program prescribed used the same equipment that was used for testing therefore some of the strength benefits may be attributed to increased familiarity with the testing equipment. (Continued )

9 Volume 37, Number 6 Nedelec et al e547 Table. (Continued ) Authors Design Sample Outcome Measures Intervention Results Level of Evidence Ebid et al RCT n = 40 (Ex = 0; SOC = 0; (01) 19 healthy = 3) Mean age (yrs): Ex = 4.6; SOC = 7.3; healthy = 4.6 Mean %TBSAB: 45.5 (range 35 55%) Baseline: 6 mos post-burn Strength (Biodex System-3 dynamometer) Ambulation speed Baseline comparison to healthy subjects Evaluated at baseline and 1 weeks later (6 and 9 mos post-burn) 1-week treatment period SOC: OT & PT Ex: 3 /wk, treadmill warm up, quadriceps and hamstrings stretching, concentric strengthening Peak knee extensor and flexor torque significantly increased for Ex group from baseline to post-training Ex group s peak torque and total work significantly improved more than SOC Peak torque and total work of healthy subjects was significantly greater than both burn survivors groups post-training Ex group ambulation speed significantly increased from baseline and compared with SOC Ambulation speed was significantly greater for healthy subjects compared with both burn survivor groups at baseline Ebid et al 19 published a RCT in 01 comparing burn survivors randomly assigned to either a 1-week isokinetic training program or a SOC group. They compared strength and ambulation speed. The exercise group demonstrated a significant improvement for all outcome measures from baseline to post-training and significantly greater improvement than the SOC group for all outcomes. A comparison of burn survivors to healthy participants revealed that healthy participants peak torque and total work was significantly greater than both groups of burn survivors post-training (9 months post-burn) and ambulation speed was significantly faster at baseline (6 months post-burn). Grisbrook et al (01) 0 Case control study n = 18 (burn survivors = 9; healthy = 9) Mean age (yrs): Burn survivors = 39; healthy = Mean %TBSAB: 4 Baseline: 6.56 yrs post-burn (range 14) Evaluation at baseline and 1 weeks Pulmonary function (Spirometry) Peak oxygen consumption (VO peak ) Canadian occupational performance measure 1-week treatment period Ex: supervised, individual goaldirected, interval training and resistance Ex sessions, 3 /5; treadmill, strengthening (Biodex System-3 Dynamometer), machine and free weights, then occupational performance-based tasks with resistance Predicted and raw FEV 1.0 /FVC ratio values were significantly lower for burn survivors compared with healthy subjects both at baseline and post-treatment No significant improvement in pulmonary function in either group after exercise training VO peak, max minute ventilation and work performed on treadmill all significantly improved posttreatment for both groups Clinically significant change in COPM post-treatment for both groups 4 (Continued )

10 e548 Nedelec et al November/December 016 Table. (Continued ) Authors Design Sample Outcome Measures Intervention Results Level of Evidence In 01, Grisbrook et al 0 conducted a case control study examining the effects of a 1-week exercise training program on pulmonary function and aerobic capacity of burn survivors compared with healthy controls. Nine burn survivors and nine healthy control participants were recruited into a supervised, individualized, occupational performance, and goaldirected training program. All burn survivors were at least years post-burn with at least a 0% surface area burn. There was a statistically significant difference in the force expiratory volume/forced vital capacity ratios of burn survivors compared with healthy controls, both at baseline and post-exercise program. After the exercise program, aerobic capacity as measured by VO peak, maximal minute ventilation and work performance on the treadmill significantly improved relative to baseline for both groups, but there was no improvement in pulmonary function for either group with time. There was also a clinically significant increase in occupational performance for both groups, thus their ability to participate in activities that were important to them and their satisfaction with their performance significantly improved. Grisbrook 4 et al (013) 37 Case control study Same as Grisbrook et al (01) Strength (Biodex System-3 dynamometer) LBM (DEXA) Same as Grisbrook et al (01) Peak torque, work, and power: reported on a subgroup of burn survivors and all nine healthy subjects: significant improvement across all muscle groups with treatment Significant increase in LBM with exercise for both groups Further analysis of the case control study published in 01 0 was published in and reported on the effect of the exercise training program on muscle strength and LBM. For the analysis, the authors combined the data of the burn survivors and nonburned healthy controls to determine the within group effect, which demonstrated an increase for all of the strength outcomes. There was no between group effect for any of the strength outcomes. They also reported that there was an increase in LBM postexercise for the group when they combined the burn survivors and healthy participants. Hardee et al (014) 38 Mean age (yrs): RCT n = 47 (Ex = 4; SOC = 3) Ex = 13; SOC = 13 Mean %TBSAB: Ex = 60; SOC = 59 Height, weight Strength (Biodex System-3 dynamometer) LBM (DEXA) Peak oxygen consumption (VO peak ) Mixed muscle fractional synthetic rate (stable isotope infusion study) 1-week treatment period beginning immediately postdischarge SOC group: OT/PT home program Ex: Figure Significant difference between groups for peak torque when corrected for body weight, VO peak, % change in LBM discharge to post treatment and whole-body, leg, arm, and % change in LBM discharge to 1 months post-burn for whole-body and leg Significant change with treatment: both Ex and SOC group s muscle fractional synthetic rate reduced between discharge and post-treatment but there was no difference between groups In 014, Hardee et al 38 conducted a RCT studying the effect of a 1-week exercise program initiated immediately after discharge from the acute care center compared with SOC, as opposed to 6 months post-burn, which was the case with all of their previous reports from this group. There was no difference between the exercise group and the SOC group at baseline for age, height, weight, TBSA burned, length of stay, or female to male ratio. After completion of the exercise program comparison between groups revealed that the exercise group had significantly greater relative peak torque, VO peak, percent change in whole-body, leg and arm LBM between discharge and post-treatment, and percent change in whole-body and leg LBM between discharge and 1 months post-burn. Both groups demonstrated a reduction in muscle fractional synthetic rate between discharge and post-treatment, which is consistent with a decrease in hypermetabolism, but there was no difference between groups, demonstrating that exercise training did not negatively affect hypermetabolism in burn survivors. (Continued )

11 Volume 37, Number 6 Nedelec et al e549 Table. (Continued ) Authors Design Sample Outcome Measures Intervention Results Level of Evidence Paratz et al Nonrandomized (01) 39 controlled follow-up study n = 30 (Ex =16; SOC = 14) Mean age (yrs): Ex = 30.4; SOC = 4.64 Mean %TBSAB: Ex = 47; SOC 9.9 Ex group: significantly younger, larger surface area burn, longer hospital and ICU stay, increase % hand burns and # of septic episodes MSWT Peak oxygen consumption (VO peak ) Strength, grip Function and quality of life (QuickDASH, LEFS, BSHS-A) 1-week treatment period SOC: self-management program of exercises and referral to local therapist Ex: supervised aerobic and resistance training Significant change with treatment: quad, latissimus dorsi, R & L grip strength, LEFS, QuickDASH Significant difference between groups: at baseline R & L grip strength; at 6 weeks quad, latissimus dorsi, VO peak, QuickDASH; at 3 mos quads, latissimus dorsi, VO peak, MSWT, QuickDASH No adverse effects reported A nonrandomized, follow-up study conducted in Australia was also reported in Burn survivors recruited into this study were assigned to the exercise plus SOC group if they lived in close proximity to the burn center to attend therapy sessions on a regular basis for a 6-week period of time or were assigned to SOC if they lived far enough from the burn center that they could only attend intermittent follow up appointments. Study outcomes included the modified shuttle walk test, VO peak, muscle and grip strength, QuickDASH, lower extremity functional scale and burn-specific health scale (BSHS) abbreviated version. At baseline, the exercise group was significantly younger, had larger surface area burns, stayed longer in the intensive care unit and hospital, less grip strength, and was twice as likely to have hand burns and septic episodes during the acute stay. For the BSHS, the motor and skills subdomain was significantly higher for the exercise group at baseline. All outcome measures significantly improved over time for the exercise group and all except VO peak, resting heart rate, shuttle distance, lower extremity functional scale and QuickDASH for the SOC group. In addition, there was no significant improvement in any of the domains or the total score for the SOC group with time, in fact the psychological domain significantly worsened with time for this group. Hand function improved for both groups with time. The group allocation procedure employed in this study makes it very difficult to conclude that the aerobic and resistive exercise training components were responsible for the difference in outcomes since there are so many differences between their baseline characteristics and the after discharge care that these patients received. However, despite the fact that the exercise group had larger burns that required longer inpatient care and were more likely to involve their hands, their improvement across time for impairment, functional and quality of life outcomes were more substantial than the SOC group that was not treated at the burn center. Thus, the overall rehabilitation program that was received by the group treated at the burn center had substantial benefits relative to the self-management SOC program. Parrott et al Historically (1988) 40 controlled study n= 40 (Ex = 0; historical controls = 0) Age range: yrs %TBSAB: range LOS Number of OT/PT visits Time returning to work Subjective questionnaire Control: 1 hrs/d OT/PT (unstructured individualized program) Ex: hrs/d of IP OT/PT (structured circuit of pulley work, bicycle work, UE ergometer, LE mat work, chin-ups, stair step work, writing on and cleaning a mirror, macramé or belt work, UE wand exercise, a pipe project) Similar LOS Ex compared with control: decreased number of OP visits and earlier return to work Positive participant feedback on questionnaire No statistical analysis Parrott et al 40 reported on a structured inpatient exercise program that was implemented for 0 adult burn survivors. This group s outcomes were then compared with a historical control group. They showed that although the length of stay for the two groups were comparable, the group who participated in the structured exercise program required less outpatient OT/PT visits and returned to work sooner, although no statistical analyses were reported. (Continued ) 3 4

12 e550 Nedelec et al November/December 016 Table. (Continued ) Authors Design Sample Outcome Measures Intervention Results Level of Evidence Porro et al RCT n = (4 groups: Ox + (01) 41 Ex = 14; Ox + SOC = 56; P + Ex = 1; P + SOC = 131) Mean age (yrs): Ox + Ex and Ox + SOC = 8; P + Ex and P + SOC = 8 (range 0 18) Mean %TBSAB: Ox + Ex and Ox + SOC = 57; P + Ex and P + SOC = 54 REE (Sensor-Medics V max 9 metabolic cart) Height, weight Whole body fat, LBM, bone mineral content, bone mineral density (DEXA) Cardiac function Sexual maturation Concentration of serum inflammatory cytokines, hormones, and liver enzymes Strength (Biodex System-3 dynamometer) Evaluated at admission, discharge, 6, 9, 1, 18, 4, 36, 48, 60, and 7 months post-burn Same as Prkzora et al (007) NOTE: only results related to exercise reported here Bone mineral content significantly differed between Ox + Ex compared with P + Ex group LBM significantly increased in Ox + Ex compared with P + Ex group at 4 to 7 mos follow-up Strength significantly greater in Ox + Ex group compared with all other groups at 9, 1, 18, and 4 mos In 01, Porro et al 4 published a long-term follow up paper to Przkora et al s article. Although this manuscript did not directly respond to our PICO question, since their focus was on the safety and efficacy of oxandrolone, it was retained since they reported on the long-term effects of oxandrolone and exercise on bone mineral content, lean body mass, and strength. Their long-term follow up results demonstrated that the muscle strength of the group that received oxandrolone and participated in the exercise program (Figure ) was significantly greater than the other three groups at 9, 1, 18, and 4 month post-burn. For children aged 7 18 years old there was a significant difference in bone mineral content and LBM compared with the exercise control group at years post-burn and at the end of the study or at 5 years post-burn. Porro et al (013) 4 Ex = 7; Ex = 31) RCT n = 58 (propranolol + Mean age (yrs): Propranolol + Ex = 13.7; Ex = 13.1 (range 7 18) Mean %TBSAB: Propranolol + Ex = 60; Ex = 60 Baseline: 6 mos post-burn Strength (Biodex System-3 dynamometer) LBM (DEXA) Peak oxygen consumption (VO peak ) Propranolol: dosage titrated to decrease resting heart rate by 15 0% from admission value Ex: (Figure ) Strength, LBM, VO peak all significantly increased with treatment for both groups Significant change in VO peak for propranolol + Ex compared with Ex Strength, LBM, VO peak percent change was significantly higher than SOC historic controls No adverse effects reported (Continued )

13 Volume 37, Number 6 Nedelec et al e551 Table. (Continued ) Authors Design Sample Outcome Measures Intervention Results Level of Evidence In 013, Porro et al 41 published a report examining the effects of propranolol and exercise. The two groups received propranolol and exercise or exercise alone with the exercise program described in Figure. There was a significant increase in muscle strength, lean body mass, and VO peak after the 1-week exercise program for both groups with the VO peak being significantly higher in the group receiving propranolol compared with exercise alone. The authors also compared both groups to historic controls who received SOC but did not participate in the exercise program and did not receive propranolol and found the exercise groups had significantly greater percent change in strength, lean body mass and VO peak. Pkzora et al (007) 1 Ox + SOC = 9; P + Ex = 17; P + RCT n = 51 (4 groups: Ox + Ex = 14; SOC = 11), Mean age (yrs): Ox + Ex = 1.1; Ox + SOC = 11.8; P + Ex = 10.9; P + SOC = 11.8 (range 7 18) Mean %TBSAB: Ox + Ex = 5.1; Ox + SOC = 54.7; P + Ex = 55.6; P + SOC = 51.6 Baseline: 6 mos post-burn Strength (Biodex System-3 dynamometer Peak oxygen consumption (VO peak ) LBM (DEXA) Hormone panel Ox or P administered discharge to 9 mos post-burn SOC: same as Suman et al (003) Ex (Figure ) NOTE: only results related to exercise reported here. No baseline differences in height, weight, LBM, strength, or VO peak Weight significantly increased in Ox + Ex group compared with all other groups and for Ox + SOC compared with P + SOC LBM showed a significant mean % change in Ex compared with SOC groups and Ox + SOC and P + Ex compared with P + SOC Ex groups showed significantly greater increases in mean % strength change than P + SOC VO peak mean % change significantly increase in Ex groups compared with SOC Using the same design and study groups as Suman et al, 43 Przkora et al 1 examined the effects of oxandrolone (instead of rhgh) and exercise on muscle strength and cardiopulmonary fitness were. There was a significant increase in body weight associated with oxandrolone and exercise compared with the other three groups and with oxandrolone alone compared with placebo. Lean body mass showed a significant mean percent increase associated with oxandrolone and exercise compared with the other three groups and with oxandrolone alone compared with placebo with exercise and placebo with SOC. Muscle strength significantly increased in all groups compared with the placebo and SOC. Aerobic capacity (VO peak ) significantly increased in both exercise groups compared with the SOC groups suggesting that oxandrolone alone has no demonstrable impact on this variable. Suman et al (00) 16 healthy = 0) RCT n = 51 (Ex = 17; SOC = 14, Mean age (yrs): healthy = 1.6; Ex = 10.6; SOC = 10.7 (range 7 18) Mean %TBSAB: Ex = 59.8; SOC = 57. Baseline: 6 mos post-burn Pulmonary function (FEV 1.0, FVC, max voluntary ventilation) Peak oxygen consumption (VO peak ) Treadmill time (modified Bruce protocol) 1-week treatment period SOC: as Suman et al (001) Ex: Figure All baseline measures of pulmonary function were significantly decreased in burn compared with healthy children Significant increases in pulmonary function and VO peak in Ex group after 1/5 Significant between groups difference for mean % change in max voluntary ventilation, treadmill time, and VO peak (Continued )

14 e55 Nedelec et al November/December 016 Table. (Continued ) Authors Design Sample Outcome Measures Intervention Results Level of Evidence In 00, Suman et al 16 published a study examining the effect of exercise training (Figure ) compared with SOC on pulmonary function. The pediatric burn survivors were randomly assigned to the exercise group or the SOC group and a group of nonburn children were included as a comparison group. At baseline, the exercise and SOC group did not differ with respect to age, percent burn surface area, height, weight, and body surface area but the non-burn groups were significantly heavier. Baseline pulmonary function was normal for the nonburn group and there was no difference in pulmonary function between the exercise and SOC group. However, all pulmonary function tests were significantly lower in the exercise and SOC groups compared with the nonburn children. After 1 weeks of exercise there was a significant increase in FEV 1, FVC and MVV with a significant between group difference (exercise vs SOC) for MVV, treadmill time, and VO peak. Suman et al (001) 3 Mean age (yrs): Ex = 10.5; RCT n = 35 (Ex = 19; SOC =16) SOC = 11 Mean %TBSAB: Ex = 59.4; SOC = 58.0 Baseline: 6 mos post-burn Height, weight Strength (Cybex dynamometer) LBM (DEXA) Peak oxygen consumption (VO peak ) REE (metabolic cart) Evaluated at baseline and 1 weeks later (6 and 9 mos post-burn) 1-week treatment period SOC: OP OT & PT x/d x 1 hr Ex: (Figure ) Significant change with treatment: Ex group mean increased change peak torque, total work, average power, LBM, VO peak, peak treadmill time; SOC group REE significantly increased from baseline Significant between group differences: mean change peak torque, total work, average work, LBM, change in treadmill time, VO peak Suman et al 3 studied the effect of a 1-week exercise program (Figure ) compared with SOC on pediatric burn survivors strength, total work average power, LBM, peak treadmill time, and peak oxygen consumption (VO peak ). Subjects were randomly assigned either to the exercise group or the SOC group. They found a significant improvement in all of these parameters, in the exercise group and a significant improvement in time when comparing between the exercise and the SOC group. Suman et al (003) 43 P + Ex = 13; GH + RCT n = 44 (GH + Ex = 10; SOC = 10; P + SOC = 11) Mean age (yrs): GH + Ex = 11.0; P + Ex = 10.5; GH + SOC = 11.5; P + SOC = 10.8 (range: 7 17) Mean %TBSAB: GH + Ex = 60.3; P + Ex = 58.5; GH + SOC = 55.9; P + SOC = 53.4 Baseline: 6 mos post-burn Height, weight Strength (Biodex System-3 dynamometer) LBM (DEXA) Fat-free mass (whole body potassium) Peak oxygen consumption (VO peak ) Hormone panel Evaluated at baseline and 1 weeks later (6 and 9 mos post-burn) rhgh or P administered postdischarge SOC: same as Suman et al (001) Ex: Figure NOTE: only results related to exercise reported here No differences height & weight between 6 and 9 mos post-burn LBM increased significantly after 1/5 in all groups except P + SOC No significant difference in fat-free mass at baseline or after 1/5 Strength (peak torque) increased significantly for GH + Ex, P + Ex, GH + SOC, and P + SOC VO peak increased significantly for GH + Ex and P + Ex but not for GH + SOC or P + SOC No side effects noted with administration of GH (Continued )

15 Volume 37, Number 6 Nedelec et al e553 Table. (Continued ) Authors Design Sample Outcome Measures Intervention Results Level of Evidence In 003, Suman et al 43 published a report examining the effect of exogenous growth hormone and exercise on LBM and muscle strength. Burned children were randomly assigned to four groups 1 day before being discharged from hospital: (1) those who received recombinant human growth hormone (rhgh) and participated in the exercise program (Figure ) that was initiated 6 months post-discharge, () those who received rhgh and SOC, (3) those who received saline placebo and participated in the exercise program that was initiated 6 months post-discharge, and (4) those who received saline placebo and SOC. During the 1-week period, there was a significant increase in LBM for all groups, with the exception of the group that received the placebo and SOC, but there was no between group differences. Strength and VO peak significantly increased in the two exercise groups but was not significantly impacted by growth hormone administration. Suman et al (007) 44 healthy = 6) RCT n = 0 (Ex = 9; SOC = 11; Mean age (yrs): Ex = 11.8; SOC = 13.4; healthy = 13.5 (range 7 17) Mean %TBSAB: Ex = 61; SOC = 56 Baseline: 6 mos post-burn Height, weight LBM (DEXA) Strength (Biodex System-3 dynamometer) Evaluated at baseline and 1 weeks later and 3 mos after exercise cessation (6, 9, and 1 mos post-burn) 1-week treatment period (6 to 9 mos post-burn) then 3 month follow-up (1 mos post-burn) SOC: same as Suman et al (003) Ex: Figure Significant weight gain in the Ex group only between 6 and 9 mos LBM mean % change: significantly increased between 6 and 9 months in the Ex group but not the SOC group; continued to significantly increase at the 1 months follow up in the Ex group compared with the SOC group Strength mean % change: significantly increased in the Ex group compared with SOC; continued to increase at the 1 months follow-up in the Ex group compared with SOC but this was not statistically significant nor were there any group differences In 007, Suman et al 44 examined the long-term effect after stopping the 1-week exercise program. The study design was similar to their 001 study 3 with the addition of a follow-up evaluation 3 months after exercise cessation (1 months post-burn). The authors reported that LBM and strength increased during the 1 week exercise program for the exercise group compared with the SOC and continued to improve after the program stopped but this later improvement was not significant. ADL, activities of daily living; AROM, active range of motion; BMI, body mass index; BSHS-A, burn-specific health scale abbreviated; BSHS-B, burn-specific health scale brief; C, control; COPM, Canadian Occupational Performance Measure; d, day; DEXA, dual-energy X-ray absorptiometry; Ex, exercise; ext, extension; FEV 1.0, forced expiratory volume; flex, flexion; FVC, forced vital capacity; GH, growth hormone; hr, hour; IGF-1, insulin-like growth factor-1; IGFBP-3, insulin-like growth factor binding protein-3; IP, inpatient; LBM, lean body mass; LE, lower extremity; LEFS, lower extremity functional scale; LOS, length of stay; mos, months; max, maximum; MWT, minute walk test; MSWT, modified shuttle walk test; n, sample size number; OP, outpatient; OT, occupational therapy; Ox, oxandrolone; P, placebo; PT, physiotherapy; RCT, randomized controlled trials; REE, resting energy expenditure; reps, repetitions; ROM, range of motion; SF-36, Medical Outcomes Study 36-Item Short Form; SOC, standard of care; TBSAB, total body surface area burned; UE, upper extremity, VO peak, peak O consumption; vs, versus;, times; W&E, Wellness and Exercise; WBV, whole body vibration; WTQ, work-to-quota; WTT, work-to-tolerance; yrs, years; /5, number of weeks; #, number; 3RM, three repetition maximum; /s, degrees per second. In all cases significant changes refers to a reported P value of <0.05.